New ways of defining protein and energy relationships in inborn errors of metabolism.

Dietary restrictions required to manage individuals with inborn errors of metabolism (IEM) are essential for metabolic control, however may result in an increased risk to both short and long-term nutritional status. Dietary factors most likely to influence nutritional status include energy intake, protein quality and quantity, micronutrient intake and the frequency and extent to which the diet must be altered during periods of increased physical or metabolic stress. Patients on the most restrictive diets, including those with intakes consisting of low levels of natural protein or those with recurrent illness or frequent metabolic decompensation carry the most nutritional risk. Due to the difficulties in determining condition specific requirements, dietary intake recommendations and nutritional monitoring tools used in patients with IEM are the same as, or extrapolated from, those used in healthy populations. As a consequence, evidence is lacking for the safest dietary prescriptions required to manage these patients long term, as tolerance to dietary therapy is generally described in terms of metabolic stability rather than long term nutritional and health outcomes. As the most frequent therapeutic dietary manipulation in IEM is alteration in dietary protein, and as protein status is critically dependent on adequate energy provision, the use of a Protein to Energy ratio (P:E ratio) as an additional tool will better define the relationship between these critical components. This could accurately define dietary quality and ensure that not only an adequate, but also a safe and balanced intake is provided.

Linear growth of children on a ketogenic diet: does the protein-to-energy ratio matter?

Ketogenic diet is a structured effective treatment for children with intractable epilepsy. Several reports have indicated poor linear growth in children on the diet but the mechanism of poor growth has not been elucidated. We aimed to explore whether the protein to energy ratio plays a role in linear growth of children on ketogenic diet. Data regarding growth and nutrition were, retrospectively, collected from the clinical histories of 35 children who were treated with ketogenic diet for at least 6 months between 2002 and 2010. Patients were stratified into groups according to periods of satisfactory or poor linear growth. Poor linear growth was associated with protein or caloric intake of <80% recommended daily intake, and with a protein-to-energy ratio consistently ≤1.4 g protein/100 kcal even when protein and caloric intakes were adequate. We recommend a protein-to-energy ratio of 1.5 g protein/100 kcal be prescribed to prevent growth retardation.

Early clinical manifestations and eating patterns in patients with urea cycle disorders.

OBJECTIVES: To characterize dietary habits and eating patterns in patients with a urea cycle disorder (UCD), and to identify dietary habits that may serve as clues to lead to earlier diagnosis of these disorders. STUDY DESIGN: This was a retrospective study of clinical and dietary data from hospital records of all patients with UCD (n = 90) attending the Royal Children's Hospital in Melbourne between 1972 and 2010. RESULTS: Protein aversion, food refusal, frequent vomiting, poor appetite, and adverse reaction to high-protein-containing foods were documented in the majority of patients with available detailed dietary protein intake data. Fourteen of the 90 admissions for metabolic deterioration in which information regarding the precipitating factor(s) were available were directly related to protein intake (5 higher and 9 lower than prescribed). CONCLUSION: Protein aversion is a common feature of UCD and may serve as a diagnostic clue in patients presenting with food refusal, recurrent vomiting, behavioral problems, mental retardation, and "unexplained" episodes of altered consciousness. Dietary history should be included in the investigation of these symptoms, which might lead to earlier diagnosis. Metabolic decompensation is more frequently related to low energy/protein intake than to high protein intake in these patients. Special attention should be given to protein aversion, which often leads to eating patterns that make it difficult for a patient to achieve the prescribed daily protein requirement.

Effect of tetrahydrobiopterin on Phe/Tyr ratios and variation in Phe levels in tetrahydrobiopterin responsive PKU patients.

BACKGROUND: Whilst a reduction in blood phenylalanine (Phe) levels is essential in patients with PKU, a decrease in Phe/Tyrosine (Tyr) ratio and fluctuations in blood Phe levels over time have been recently associated with improved neuropsychological outcome. The aim of this study was to identify if Tetrahydrobiopterin (BH(4)) offers additional benefit based on the assumption that these 2 factors are beneficial. METHOD: Since 2002, 9 patients identified through NBS as BH(4) responsive (BH(4) group) and 25 non-responsive patients (non-BH(4) group) produced a total of 1384 and 4415 samples, respectively, for analysis. Statistical analysis was performed to compare mean and median Phe levels, Tyr levels and Phe/Tyr ratios in BH(4) and non BH(4) responsive patients. RESULTS: Variations in blood Phe levels were greater in the non-BH(4) group (BH(4): median 338 µmol/L, 95% Confidence Interval (CI) 329-346, mean: 358 µmol/L, CI 350-366; non-BH(4): median 338 µmol/L CI 332-344, mean: 370 µmol/L CI 364-376). Variations in blood Tyr levels were slightly greater in the non-BH(4) group: (BH(4): median 59 µmol/L CI 58-61, mean 67 CI 66-69; non-BH(4): median 62 µmol/L CI 61-63, mean 70 CI 69-71). The variation in Phe/Tyr ratios was greater in the non-BH(4) group (mean 6.12, CI 5.9-6.3) than in the BH(4) group (Mean 5.44, CI 5.3-5.6), particularly at blood Phe levels >600 µmol/L. CONCLUSION: BH(4) responsive patients have smaller variations in blood Phe levels and tighter Phe/Tyr ratios than non-BH(4) responsive patients, particularly at high blood Phe levels. If decreased fluctuations in Phe levels and a decreased Phe/Tyr ratio are indeed neuro-protective, then BH(4) responsiveness is advantageous over diet alone in PKU. Neuropsychological testing in patients who have been treated with BH(4) long term may be able to ascertain the clinical benefit of these biochemical findings.

Newborn screening for glutaric aciduria type I in Victoria: treatment and outcome.

Between October 2001 and September 2007, a total number of 391,651 neonates were screened in Victoria using Tandem Mass Spectrometry and 6 newborns were diagnosed as having GA I, giving an incidence of 1:65,275 (CI: 1:29,988=1:177,861). Another patient was diagnosed through cascade screening of children born before the implementation of the expanded newborn screening program. Patients were treated by mild protein restriction (2-2.5 g/kg/day) and carnitine supplementation when well, focussing on the aggressive management of intercurrent illnesses (temporary cessation of protein intake, increase in calorie intake, IV carnitine, aggressive anti febrile and anti infectious treatment), including prophylactic admissions to hospital. Overall, our patients had 35 admissions to hospital, of which 15 were in the first year of life. None had a post infectious dystonic syndrome. Neuropsychological examinations revealed normal to high cognitive and gross motor function in all patients but one, with some deficiencies in fine motor activities and different levels of speech abnormalities in all patients. Since therapeutic approaches for GA I, although not uniform, are well established and have been documented to be effective, newborn screening for this disorder should prove justified. A therapeutic approach of dietary modification, IV carnitine and aggressive treatment of intercurrent illness seems to prevent the severe neurological complications of GA I. More in-depth consideration of speech and language function is necessary to document specific deficits in children with GA I and plan proactive interventions.

Three-year audit of the hyperphenylalaninaemia/phenylketonuria spectrum in Victoria.

AIMS: To determine the prevalence, the types and severity of hyperphenylalaninaemia (including phenylketonuria (PKU)) in Victoria and to report on a new treatment modality of PKU. METHODS: We reviewed the medical records of all patients diagnosed with high blood phenylalanine levels by newborn screening between November 2001 and October 2004. RESULTS: We identified 17 newborn babies with high levels of blood phenylalanine (total samples: 190,835). Dihydrobiopterin reductase deficiency was excluded in all babies. Five babies had persistent phenylalanine levels of 200-300, and do not receive any dietary or pharmaceutical therapy. One baby was diagnosed as having pyruvoyl tetrahydro-pterin synthase deficiency. Following reports of tetrahydrobiopterin (BH(4))-responsive PKU, we have performed a BH(4) load (20 mg/kg, 6R-5,6,7,8-tetrahydro-L-biopetrin dehydrochloride; Schricks Laboratories, Jona, Switzerland) in 10 newborn babies with PKU (one baby with a phenylalanine level of 2600 micromol/L was started on diet without prior load). Three babies had a significant response to BH(4) (>35% decrease in phenylalanine level). Protein restriction (1.2 g/kg/day) and introduction of phenylalanine-free formula, in addition to BH(4) treatment, were necessary in one patient. The other patients maintain good metabolic control with BH(4) treatment only (at approximately 11 mg/kg/day) and an intake of 2-3 g protein per day. Of the nine babies who are on a full PKU diet, three have high phenylalanine tolerance (consistently >40 mg/kg/day). CONCLUSION: There is a spectrum of severity of hyperphenylalaninaemia in the population. The detection of BH(4)-responsive PKU patients offers them a less restrictive dietary regimen and an improved quality of life, and may enable near normal life-style in adolescence.

The ketogenic diet in refractory childhood epilepsy.

OBJECTIVE: To report the efficacy and tolerability of the ketogenic diet (KD) in refractory paediatric epilepsy. METHODS: Twenty-six consecutive children were treated with the classical KD from 1996 to 2001. The epilepsy syndromes included symptomatic generalized epilepsy (15), idiopathic generalized epilepsy (4), symptomatic partial epilepsy (1) and unclassified epilepsy (6). One child was lost to follow up. RESULTS: Median age at initiation of the KD was 6.1 years. Median duration of the treatment was 9 months. Twelve children (48%) were treated for >12 months; one still remains on the KD. Four children (16%) became seizure-free. Five children (20%) had 50-99% reduction in seizures, seven (28%) had <50% reduction in seizures and eight (36%) had no improvement. Age, seizure-type and aetiology did not predict response. The medications were decreased in 33% of the children. The KD was discontinued in 64% of the children because of poor efficacy and in 12% because of side-effects. Problems during initiation of the KD included asymptomatic hypoglycaemia (24%) and vomiting (12%). Later complications included poor growth (20%), hyperlipidaemia (16%), hypercalcuria (8%), hypocarnitaemia (8%), constipation (8%), pancreatitis (4%) and decreased bone density (4%). There were no deaths. A 3-month trial of the KD costs A3879 dollars. The first 12 months cost A7275 dollars with a cost of A4528 dollars each year, thereafter. CONCLUSIONS: The KD is an effective treatment for some children with refractory epilepsy, being generally well tolerated and rarely associated with side-effects. Response is not necessarily predicted by age, syndrome or aetiology. A prospective study of the KD is presently underway.

Megestrol acetate in pediatric oncology patients may lead to severe, symptomatic adrenal suppression.

BACKGROUND: Despite the widespread use of megestrol acetate (MA) among a growing number of pediatric oncology departments, there is only one published study on the use of MA in children with malignant disease. The objectives of the current study were to examine the effect of MA in improving the nutritional status of children with malignant disease and to describe and consider the implications of MA-associated adrenal suppression that was found consistently. METHODS: Medical records of 19 children with malignant disease who were treated with MA were reviewed. During MA therapy, clinical assessments every 4 weeks included anthropometrics, caloric intake, quality-of-life scores, and appetite scores. Serum cortisol levels, lipid profiles (including cholesterol levels) random blood glucose levels, and coagulation screening were measured at 4-6-week intervals. RESULTS: MA use was associated with significant increases in weight, weight z score, middle-upper arm circumference, triceps skin-fold thickness, appetite, and caloric intake. MA was extremely useful in aiding the efficient tapering of nasogastric feeds. However, a significant and potentially dangerous decrease in cortisol was seen in 10 of 11 patients tested, with 1 patient who manifested clinical hypoadrenalism with hemodynamic collapse, requiring inotropic support. This is the first report of MA-associated clinical adrenal suppression in a child with malignant disease. CONCLUSIONS: Although the results of this study support the ability of MA to improve nutritional status, its use was complicated by severe adrenal suppression in almost all patients tested, with a serious clinical adverse event occurring in one patient. Routine hydrocortisone supplementation throughout MA treatment should be considered as well as larger doses for patients with acute illness and patients who undergo surgery.